Download Screening for Lipid Disorders in Adults

Evidence Synthesis___________
Number 49
Screening for Lipid Disorders in Adults:
Selective Update of 2001
U.S. Preventive Services Task Force Review
Prepared for :
Agency for Healthcare Research and Quality (AHRQ)
U.S. Department of Health and Human Services
540 Gaither Road
Rockville, MD 20850
www.ahrq.gov
Investigators:
Mark Helfand, MD, MPH, FACP
Director, Oregon Evidence-based Practice Center
Oregon Health and Science University
3181 SW Sam Jackson Park Road
Portland, Oregon 97239
[email protected]
Susan Carson, MPH
Senior Research Associate, Oregon Evidence-based Practice Center
Oregon Health and Science University
3181 SW Sam Jackson Park Road
Portland, Oregon 97239
[email protected]
AHRQ Publication No. 08-05114-EF-1
June 2008
Disclaimer
This report is based on research conducted by the Oregon Evidence-based Practice Center (EPC)
under contract to the Agency for Healthcare Research and Quality (AHRQ), Rockville, MD
(Contract No. 290-02-0024). The investigators involved have declared no conflicts of interest
with objectively conducting this research.
The findings and conclusions in this document are those of the author(s), who are responsible for
its content, and do not necessarily represent the views of AHRQ. No statement in this report
should be construed as an official position of AHRQ or of the U.S. Department of Health and
Human Services.
The information in this report is intended to help clinicians, employers, policymakers, and others
make informed decisions about the provision of health care services. This report is intended as a
reference and not as a substitute for clinical judgment.
This report may be used, in whole or in part, as the basis for the development of clinical practice
guidelines and other quality enhancement tools, or as a basis for reimbursement and coverage
policies. AHRQ or U.S. Department of Health and Human Services endorsement of such
derivative products may not be stated or implied.
Suggested citation:
Helfand M, Carson S. Screening for Lipid Disorders in Adults: Selective Update of 2001 U.S.
Preventive Services Task Force Review. Evidence Synthesis No. 49. Rockville, MD: Agency for
Healthcare Research and Quality, April 2008. AHRQ Publication no. 08-05114-EF-1. Available
at http://www.ahrq.gov/downloads/pub/prevent/pdfser/lipides.pdf
ii
ABSTRACT
Purpose: Both the US Preventive Services Task Force (USPSTF) and the National Cholesterol
Education Program (NCEP ATP III) have issued recommendations on screening for
dyslipidemia in adults. To guide the USPSTF in updating its 2001 recommendations, we
reviewed evidence relevant to discrepancies between these recommendations.
Data Sources: A 2001 evidence review prepared for the USPSTF, supplemented by searches of
the Cochrane Library, MEDLINE, EMBASE, and reference lists of recent systematic reviews.
Study Selection: Randomized controlled trials and observational studies published between
December 1999 and February 2005 that addressed screening in younger patients not at high risk;
use of triglyceride levels in an initial screening panel; optimal screening intervals; selection of
patients for treatment; and harms of drug therapy.
Data Extraction: We abstracted data on the design, results, and quality of each included trial.
We used standard USPSTF methods to rate the internal validity of trials and epidemiologic
studies.
Data Synthesis: New evidence relevant to discrepancies between USPSTF and ATP III
recommendations was summarized in the context of earlier evidence.
Limitations: This document should be read in conjunction with the full systematic evidence
review conducted for the USPSTF in 2001, the final report of ATP III, and the 2004 ATP III
update.
Conclusions: There is no new evidence relevant to screening younger adults or to appropriate
screening intervals. Evidence is conflicting regarding the additional contribution of a serum
triglyceride level to the identification of individuals at short-term risk for coronary heart disease
events. The balance of benefits and harms is clearly in favor of statin therapy among individuals
enrolled in some, but not all, randomized trials of primary prevention. The long-term harms of
statin therapy are unknown.
iii
CONTENTS
Introduction..............................................................................................................1
Methods....................................................................................................................2
Results......................................................................................................................3
Limitations and Conclusions..................................................................................10
References..............................................................................................................11
Tables
Table 1. Discrepancies in 2001 USPSTF and 2002/2004
ATPIII Guidelines................................................................................................14
Table 2. Statin Trials That Included a Primary Prevention Group .......................16
Appendixes
Appendix 1. Search Strategy .................................................................................17
Appendix 2. USPSTF Quality Rating Criteria.......................................................18
Appendix 3. Selected Evidence from the May 2003 AHRQ Evidence
Report on the Diagnosis and Treatment of Coronary Heart Disease
In Women.............................................................................................................20
iv
INTRODUCTION
In 2001, the US Preventive Services Task Force (USPSTF)1 recommended that all men aged 35
and older, women aged 45 and older, men aged 20 to 35, and women aged 20 to 45 who are at
increased risk for coronary heart disease (CHD) be screened for total cholesterol (TC) and high
density lipoprotein cholesterol (HDL-C).1 In 2002, the National Cholesterol Education Program
(NCEP) published new guidelines (Adult Treatment Panel III [ATP III]) for the diagnosis and
management of lipid disorders.2, 3 The NCEP guidelines were updated in August 2004 to include
evidence from more recent trials.4
Both the USPSTF and ATP III embrace the principle that, in the short term, the benefits of
screening and treatment depend on reducing the risk of major CHD events; that is, sudden
coronary death or myocardial infarction (MI). They agree that treatment decisions should be
based on the overall risk of having an event, not on lipid levels alone, and both recommend using
Framingham5 projections to estimate risk.
The USPSTF and ATP III guidelines agree on many essential points, but there are also important
differences between them (Table 1). The USPSTF recommendations1 address screening in
asymptomatic adults who have no history of coronary heart disease. The scope of the NCEP
guidelines2, 3 is much broader. Management of patients with known heart disease, a major
subject of the NCEP guidelines, is not relevant to the USPSTF. They also differ in their
recommended target populations for screening, initial screening panel, frequency of screening,
and criteria for initiating lipid-lowering therapy.
The purpose of this selective review was to guide the USPSTF in updating its 2001
recommendations. With input from the Agency for Healthcare Research and Quality (AHRQ),
the USPSTF decided that it was critical to update only the parts of the Key Questions that pertain
to discrepancies between the USPSTF recommendations and the most recent ATP III guidelines:
1) How frequent is elevated TC in men younger than age 35 and women younger than
age 40, and what proportion have an overall 10-year risk of cardiac events of 10% or
greater?
2) What evidence supports the use of triglyceride levels as part of an initial screening
panel?
3) What are the optimal screening intervals in the general population and in patients at
high risk for CHD events?
4) What risk factors should be used to select patients for lipid-modifying drug therapy?
5) What is the current evidence about the harms of drug therapy for lipid disorders?
1
METHODS
Data Sources
The 2001 systematic evidence review prepared for the USPSTF6 was based on searches of
MEDLINE (1994 to December 1999) and the Cochrane Controlled Trials Registry through
December 1, 1999. For this update, we searched the Cochrane Library (2004, Issue 4),
MEDLINE (1966-February Week 1 2005), EMBASE (1980-February 4, 2005), PREMEDLINE
(through February 9, 2005), and dossiers submitted by manufacturers of statins (Appendix 1). To
identify key articles about the epidemiology, natural history, and detection of lipid levels and
lipid disorders, we relied on the reference lists of the 2002 ATP III Final Report2 and the 2004
update to ATP III4, as well as recent systematic reviews,7-9 supplemented by a title and abstract
search of MEDLINE and PREMEDLINE. All searches were restricted to articles published in
English.
Study Selection
We reviewed randomized trials of at least a 1-year duration that examined drug therapy with
statins among patients without previously known CHD, and measured clinical end points
including total mortality, CHD mortality, and nonfatal MI. To be included, the trial had to
address primary prevention in the general population or in a subset of the general population
identified on the basis of risk factors for CHD. We also included observational studies of the
epidemiology of lipid disorders, screening to detect lipid disorders, risk factors for CHD, and the
harms of statin therapy.
Data Extraction and Quality Assessment
Our methods for abstracting information about the design, results, and internal validity of each
included trial are described elsewhere.10 We used text and internal validity ratings from a
previous review of statins10 to summarize the results of recent statin trials and of the safety of
statins. We used standard USPSTF methods to rate the internal validity of trials and
epidemiologic studies included in this update but not in the statins review (See Appendix 2).
Data Synthesis and Analysis
We summarized new evidence relevant to discrepancies between USPSTF and ATP III
recommendations in the context of earlier evidence from the 2001 evidence review conducted
for the USPSTF, the final report of ATP III, and the 2004 ATP III update
2
Funding
This study was funded by AHRQ under Contract Number 290-02-0024, Task Order Number 2,
for the USPSTF, and by the Drug Effectiveness Review Project.
RESULTS
Key Question 1. How frequent is elevated total cholesterol in men younger than
age 35 and women younger than age 40, and what proportion have an overall 10year risk of cardiac events of 10% or greater?
ATP III recommends screening all men and women aged 20 and above, and points out that
young adults who are in the upper quartile of cholesterol levels are at high long-term risk of
cardiac mortality. The USPSTF in 2001 recommended selective screening of younger men and
women who smoke, have a history of hypertension, or have diabetes mellitus. They argued that,
in young adults without specific cardiovascular risk factors, the absolute reduction in risk as a
result of treating dyslipidemia is small. They recommended that all patients, regardless of lipid
levels, should be offered counseling about the benefits of eating a diet low in saturated fat and
high in fruits and vegetables, engaging in regular physical activity, avoiding tobacco use, and
maintaining a healthy weight.
A minority of men younger than 35 and women younger than 45 are candidates for lipidlowering therapy. Based on National Health and Nutrition Examination Survey (NHANES) III
data (http://www.cdc.gov/nchs/about/major/nhanes/nh3data.htm) in the general US population,
8.9% of men aged 18-35 and 12.3% of women aged 18-45 have a TC>240 mg/dL. Among men
aged 18-35 and women younger than 40 who do not smoke, do not have a history of
hypertension, and do not have diabetes mellitus, no combination of ATP-III risk factors (TC up
to 310 mg/dL, HDL-c, and systolic blood pressure) would result in a predicted 10-year risk of
major cardiovascular events greater than 10%. Some men younger than 35 years of age who
smoke, and those who have diabetes, have a 10-year risk that exceeds 10%, but these men can be
identified for lipid testing based on their history. In NHANES, among all nondiabetic women
aged 40-45 years, the probability of being at intermediate risk or high risk were 1.45% and 0%,
respectively; all of these women had a history of hypertension or smoking.
No new evidence examines whether targeting young adults in the upper quartile of risk is more
effective than recommending a healthy diet, physical activity, avoidance of tobacco products,
and maintenance of a healthy weight to all.
3
Key Question 2. What evidence supports the use of triglyceride levels as part of
an initial screening panel?
Both the USPSTF and ATP III recommend screening with a panel that includes a TC and HDLC, and both recommend using the average of two readings to estimate the TC and HDL-C more
accurately. ATP III recommends that the initial screening lipid panel should also include a
triglyceride level, while the USPSTF recommends obtaining a second lipid panel that includes a
triglyceride level if the initial screening results indicate that the patient is at high risk.
The 2001 USPSTF systematic evidence review found: 1) mixed, inconclusive evidence that
triglycerides are independently associated with an increased risk of CHD, and 2) insufficient
evidence to conclude that treating persons with isolated increased triglycerides would reduce
future CHD events.
Triglyceride level was not a consistent independent predictor of incident CHD events in
prospective studies conducted in middle-aged, relatively low and moderate-risk populations.
The Framingham Study5 and European Systematic Coronary Risk Evaluation (SCORE)11 risk
scoring systems do not include a measure of serum triglycerides, but a risk score derived from
the Prospective Cardiovascular Munster (PROCAM) cohort does.12, 13 The PROCAM risk score
was derived from 10-year follow-up of 5,389 German men 35 to 65 years of age. In this
relatively low-risk population, triglyceride levels were an independent predictor of coronary
events after adjustment for age, low-density lipoprotein cholesterol (LDL-C), HDL-C, systolic
blood pressure, smoking history, family history of heart attack in a first-degree relative before
age 60 years, and diabetes. In an original data meta-analysis of 26 Asian Pacific cohorts
(n=96,224), triglyceride levels were associated with coronary events and with stroke after
adjustment for age, sex, systolic blood pressure, smoking status, and total-to-HDL cholesterol
ratio.14 However, most of the cohorts included in the Asia Pacific analysis did not have
sufficient data to adjust for the other risk factors that contribute to the Framingham risk score.
Other cohort studies did not find triglycerides to be an independent predictor of coronary events
or of stroke. In the CUORE study, a pooled analysis of 11 Italian cohorts (n=6,865), triglyceride
levels were not an independent predictor of coronary events.15 The best proportional hazards
equation included age, total cholesterol, systolic blood pressure, cigarette smoking, HDL
cholesterol, diabetes mellitus, hypertension drug treatment, and family history of CHD. The
coefficients of the CUORE model agreed with those of the Framingham Heart Study. However,
the CUORE coefficients for triglyceride levels and for HDL-C differed from those of the
PROCAM model. Forcing triglyceride level into the CUORE model reduced the influence of
HDL-C and age but did not improve overall prediction. This finding was similar to that of an
analysis from the Nurses Health Study that found that a fasting triglyceride level did not provide
additional prediction of coronary events after adjustment for other lipid parameters, particularly
HDL-C.16 In an 11-year cohort study of 12,089 black and white middle-aged individuals
followed in the Atherosclerosis Risk in Communities (ARIC) population, triglyceride level was
not correlated with cardiovascular events (coronary events or stroke) after adjustment for
Framingham risk factors and components of the metabolic syndrome. Except for the triglyceride
level, every component of the metabolic syndrome (elevated blood pressure, low HDL-C,
elevated fasting glucose, and large waist circumference) was associated with a higher risk of
coronary events.17
4
These results suggest that, although the triglyceride level is a strong univariate predictor of CHD
events, its association with such events is reduced substantially by adjustment for other risk
factors. ATP III argues that, if this is true, triglyceride level may be a marker for atherogenic
remnant lipoproteins, other lipid risk factors (small LDL particles and low HDL), nonlipid risk
factors (elevated blood pressure), and emerging risk factors (insulin resistance, glucose
intolerance, prothrombotic state). That is, even if it is not an independent risk factor, if it is a
marker for these non-traditional risk factors, a triglyceride level may identify individuals at high
cardiovascular risk who might otherwise be missed. Specifically, elevated triglycerides (and the
metabolic syndrome) might identify individuals at high long-term risk of developing
cardiovascular disease who have not yet developed enough atherosclerotic disease to have a high
short-term risk of events.
Would these patients benefit from treatment for elevated triglyceride levels? Older evidence on
this question is inconclusive,6 as are recent clinical trials. Because statins, like some other
classes of lipid-lowering drugs, reduce triglyceride levels as well as LDL-C levels, they cannot
help determine how much of the benefit is due to lowering triglycerides. In the future, clinical
trials of drugs that selectively reduce triglyceride levels may determine whether targeted therapy
for hypertriglyceridemia can reduce the short-term risk of cardiovascular events in people who
have already developed lesions. However, such trials do not address whether screening for high
triglycerides can prevent the development of cardiovascular disease in the long-term. We
identified no trials with clinical endpoints that enrolled patients with elevated triglyceride levels
who would not otherwise qualify for treatment.
ATP-III also argues that initial testing should include a triglyceride level to improve the accuracy
of the TC and HDL tests. Specifically, with adjustment for the triglyceride level, elevated LDL
will be more frequently detected, and the HDL determination will be slightly more accurate. We
did not seek new evidence on these points, which were addressed in detail in the 2001 USPSTF
review.
Key Question 3. What are the optimal screening intervals in the general
population and in patients at high risk for CHD events?
We did not identify new evidence relevant to the appropriate interval to screen for
hyperlipidemia in the general population, or in subgroups of the general population.
Key Question 4. What risk factors should be used to select patients for drug
therapy?
Treatment Decisions in Relation to Overall Risk and LDL-C Levels
Treatment decisions depend not only on the LDL-C level but also on the number and nature of
other cardiac risk factors. ATP II defined three risk groups based on their history and risk status.
5
The three risk groups had different LDL-C goals and different intensities of LDL-lowering
therapy. In 2001, the USPSTF endorsed the ATP II guidelines, which identified high LDL
cholesterol as a potential target for LDL-lowering drug therapy for persons with multiple risk
factors whose LDL levels are high (>160 mg/dL) after dietary therapy, and for persons with 0-1
risk factors whose LDL levels are >190 mg/dL after dietary therapy.
As described in Table 1, in ATP-III the decision to treat depends on the presence of CHD or
CHD equivalents, the LDL-C level, and the 10-year risk of events. The CHD group now
includes persons who have a history of coronary disease as well as other persons who have an
absolute 10-year risk for developing major coronary events (myocardial infarction and coronary
death) >20%. ATP III also expanded the concept of a “CHD risk equivalent,” which refers to
persons without established CHD who should be treated in the same manner as those who have
established CHD. The CHD risk equivalents are diabetes, clinical manifestations of noncoronary
forms of atherosclerotic disease (peripheral arterial disease, abdominal aortic aneurysm, and
carotid artery disease; that is, transient ischemic attacks or stroke of carotid origin or 50%
obstruction of a carotid artery); or 2 or more risk factors with a 10-year risk for hard CHD events
> 20%. Compared with ATP-II, in ATP III many of these risk categories are assigned a lower
threshold for initiating drug therapy and a lower target LDL-C level.
Table 2 describes trials of statins, conducted in outpatient or community settings, which included
at least some subjects who had no history of coronary artery disease. Except for AFCAPS and
WOSCOPS, all of these trials were published since the 2001 USPSTF guidelines were released.
Longer-term follow-up results from WOSCOPS, published in October 2007, confirm the
persistence of a beneficial decrease in coronary events over ten years after the end of the trial in
men with elevated cholesterol but without a previous myocardial infarction.18 The reader is
referred to the 2004 ATP III update4 for a more detailed description of major recent trials.
As of 1999, randomized trials of the benefits of lipid-lowering therapy in people without
established CHD enrolled primarily middle-aged men of European descent.19-22 Many of the
trials in Table 2 enrolled subjects who were under-represented in earlier trials. For example, the
Heart Protection Study (HPS) targeted individuals in whom the risk and benefits of cholesterol
lowering were uncertain (women, those over 70 years, diabetics, those with non-coronary
vascular disease, and those with average or below-average cholesterol).23, 24 In ASCOT-LLA
(Anglo-Scandinavian Cardiac Outcomes Trial—Lipid-lowering Arm), about 24.5% of the
subjects were diabetics. CARDS (Collaborative Atorvastatin Diabetes Study) was conducted in
patients with type 2 diabetes without elevated cholesterol levels (LDL <107 mg/dL).25 Patients
had no history of cardiovascular disease but at least one of the following risk factors:
retinopathy, albuminuria, current smoking, or hypertension.
In ALLHAT-LLT (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack—
Lipid-lowering Arm),26 nearly half the subjects were women, 35% were diabetic, 15% had a
history of CHD, and about 35% were black. Pravastatin did not reduce all-cause mortality or
cardiovascular event rates. The reason for the lack of benefit of pravastatin in ALLHAT-LLT is
unclear, but the high rate of use of statins in the control group is frequently cited as a possible
explanation.
6
The good-quality Prospective Study of Pravastatin in the Elderly at Risk (PROSPER) trial was
designed to examine the benefits of statin therapy in women and in the elderly.27 Overall,
pravastatin reduced the composite primary endpoint (CHD death, nonfatal MI, fatal/nonfatal
stroke) from 16.2% in the placebo group to 14.1%. There was also a reduction in transient
ischemic attacks, but not in strokes, in the pravastatin group. There was no effect on all-cause
mortality, which was 10.5% in the placebo group vs. 10.3% in the pravastatin group. The
reduction in coronary heart disease deaths in the pravastatin group (absolute risk reduction 24%;
95% CI 1% to 42%) was balanced by an increase in cancer deaths (absolute risk increase 28%;
95% CI 3% to 68%).
In the recent SPARCL trial,28 4,731 patients who had had a stroke or transient ischemic attack in
the past one to six months were randomized to high-dose atorvastatin (80 mg) or placebo. After
a median 4.9 years of follow-up, there was a 2.2% absolute reduction in the primary endpoint of
fatal or nonfatal stroke (Adjusted hazard ratio 0.84; 95% CI 0.71 to 0.99). There was also a
reduction in risk of major cardiovascular events, but an increase in the incidence of hemorrhagic
stroke (Adjusted hazard ratio 1.66; 95% CI 1.08 to 2.55).
The results of these recent trials support the idea that patients who have “CHD risk equivalents”
benefit from lipid-lowering therapy similar to that used in individuals who have known CHD.
Treatment Decisions in Women
It is clear that lipid-lowering therapy, particularly statins, significantly reduced the risk of
coronary events among women who have a history of coronary disease or diabetes.8, 25, 29, 30
However, data for asymptomatic women who have no known coronary disease are not
conclusive.
Although only one of the first 4 primary prevention trials (AFCAPS) enrolled postmenopausal
women, the USPSTF in 2001 decided that the benefits could be extrapolated to women whose
risk of CHD events was similar to that of the trial participants. The USPSTF recommended
screening for women beginning at age 45 years, when the average risk of CHD events is similar
for that of men at 35 years of age. For the elderly, younger adults, and other groups not well
represented in the trials, the USPSTF recommended treatment for patients whose risk of CHD
events was 0.6% to 1.5% per year, the range observed in the first four primary prevention trials
of drug therapy for hyperlipidemia available in 1999. Because recent trials enrolled only highrisk enrollees, they do not provide evidence that the low end of this range should be changed.
A 2003 systematic review conducted by the University of California San Francisco–Stanford
University Evidence-based Practice Center found that 15,917 women had been included in
randomized controlled-trials (RCTs) of various lipid-lowering treatments.7 Four of these trials22,
31-33
enrolled women (n=7,673) without prior CHD (primary prevention). The characteristics of
these trials, their results, and the results of a meta-analysis are shown in Appendix 3. In the
meta-analysis for the primary prevention studies (Appendix 3, Results table, right panel),
“…there was insufficient evidence of reduced risk of any clinical outcome in women.” In the
secondary prevention studies, women had statistically significant reductions in CHD mortality,
7
CHD events, nonfatal MI, and revascularization; their magnitude was similar to those for men.
The risk for total mortality was not lower in women treated with lipid lowering, regardless of
whether they had prior CHD or not. In a more recent meta-analysis of primary prevention trials,
the pooled relative risk reduction for women was 0.87 (95% CI: 0.69 to 1.09).34 Another trial,
PROSPER, included a mixture of primary and secondary prevention populations. PROSPER
revealed that pravastatin was more effective in men than in women.27 There were 3,000 women
in the study. The baseline risk in men (n=2,804) was higher; in the placebo group, almost 20%
of men and 13% of women had an event (CHD death, nonfatal MI, or stroke) over the 3 years of
the study. For men, there was a statistically significant reduction in the primary endpoint
(Hazard ratio 0.77, CI 0.65-0.92). For women, there was no apparent effect (Hazard ratio 0.96,
CI 0.79-1.18).
Treatment Decisions in Older Patients
Although evidence from primary prevention studies is lacking, recent secondary prevention trials
deliberately recruited subjects 65 years and older to determine whether they benefit from lipidlowering therapy. In the HPS, for example, simvastatin reduced major vascular events (28.7%
vs. 23.6%) in subjects 70 years and older, and, in subjects aged 75 to 80 years at study entry, the
benefit was even greater (32.3% vs. 23.1%; P<.001).24
In one meta-analysis of the 6 secondary prevention trials that have reported results for subjects
65 years and older, statins reduced all-cause mortality by 15%.8
Treatment Decisions in Other Demographic Subgroups
Since 2001, few additional data are available from randomized trials on the effectiveness of
lipid-lowering therapy in blacks and other racial and ethnic groups. In ALLHAT,26 38% of the
subjects were black, but ALLHAT was a negative trial in which there was no difference between
the treatment and control groups for any subgroup.
Key Question 5. What is the current evidence about the harms of drug therapy
for lipid disorders?
The large randomized trials summarized above provide strong evidence about the balance of
benefits and harms from drug therapy, particularly statins. Because they were analyzed on an
intention-to-treat basis, the benefits in subjects who tolerated and complied with medication are
diluted by the lack of benefit in subjects who discontinued medication because of side effects or
did not complete the study for other reasons. Moreover, the mortality results of the trials indicate
clearly that, for the enrolled subjects, and for the duration of the trials, statins are beneficial. The
balance of benefits and harms of statin drugs over a longer time than the trials have observed
remains unclear.
8
As strong as they are, these results do not ensure that the trial results are generalizable to
individuals who would not meet the eligibility criteria for the trial. Some experts have voiced
an additional concern, that broader use of statins and more aggressive therapy to meet lower
LDL-C targets could lead to higher rates of serious harms than have been observed in trials.
Statins have rare but serious harms, especially in groups with identifiable risk factors for such
events. Statin use is associated with a range of abnormalities, from mildly elevated serum
creatine phosphokinase (CPK) levels, to myalgia, temporary or persistent muscle weakness, and
rhabdomyolysis. Mild elevations in CPK are not well-studied because controlled trials usually
record only markedly elevated levels as adverse events.
Myopathy is the best-studied harm. In placebo-controlled and direct comparison trials, rates of
muscle complaints range from 1% to 4%.10, 35 In the major clinical trials, rhabdomyolysis is
uncommon. A 2003 review summarized published literature as well as data from the Food and
Drug Administration (FDA) adverse event reporting system.35 In 28 trials combined there were
49 cases of myositis and 7 cases of rhabdomyolysis among 42,323 patients randomized to a
statin, versus 44 cases of myositis and 5 of rhabdomyolysis among 41,535 patients randomized
to placebo or to usual care.35 In the A to Z trial,36 which enrolled post-MI patients, there was a
high incidence of myopathy (9 cases, 3 with rhabdomyolysis) in patients treated with simvastatin
80 mg/d. There were no cases of myopathy with the 20 mg or 40 mg doses. The incidence of
fatal rhabdomyolysis is estimated from FDA reports at 0.15 per 1,000,000 prescriptions.
Data from pre-marketing trials suggest that higher doses of statins are associated with higher
rates of myopathy. These data are summarized in an FDA letter released in March 2005
(available at: http://www.fda.gov/cder/drug/infopage/rosuvastatin/crestor_CP.pdf. See Figure 1
and the following discussion).37 This FDA document also estimates the frequency of voluntarily
reported cases of rhabdomyolysis in the 6 months interval post-approval, ranging from 0 to 0.3
per 100,000 prescriptions (page 13).
Concomitant use of certain medications, including, for some statins, those that interact with the
CYP3A4 pathway, increase the risk of rhabdomyolysis, as do other systemic lipid-lowering
agents such as niacin and fibrates.
In controlled trials, among patients who have no history of liver disease, up to 2% of patients
have elevation of liver enzymes (transaminases, primarily Alanine aminotransferase) > 3 times
the upper limit of normal. Two meta-analyses of clinical trials9, 38 as well as the HPS24 found
rates of elevated transaminases to be no higher among patients taking statins than among those
receiving placebo. A review focusing on lovastatin found that rates of Alanine aminotransferase
levels 3 times the upper limit of normal were dose-dependent; the rate was 2.6% at 20 mg/day
and 5% at 80 mg/day.39 The rate of hepatitis was 9.7 per million patient-treatment years, and the
rate of liver failure (1 per 1.14 million patient-treatment years) was equivalent to the background
rate of idiopathic acute liver failure. Similarly, in a trial of two doses of atorvastatin, the
incidence of persistent elevations in liver aminotransferase levels was 2 per 1000 in patients
taking atorvastatin 10 mg daily, versus 1.2 per 1000 in patients taking 80 mg daily.40
9
LIMITATIONS AND CONCLUSIONS
In this selective update, we reviewed new evidence available since the publication of the
USPSTF 2001 recommendations on screening for lipid disorders in adults. This document
should be read in conjunction with the full systematic evidence review conducted for the
USPSTF in 2001, the final report of ATP III, and the 2004 ATP III update. These other reports
provide more detailed and thorough analysis than can be provided here. The main findings of
this update, focusing on discrepancies between the USPSTF recommendations and ATP III and
summarized in Table 1, should be viewed in this context.
Little new evidence directly addresses the discrepancies between ATP-III and the 2001
USPSTF recommendations. No new evidence examined whether targeting young adults at
high risk is more effective than recommending healthy lifestyle behaviors to all. Another
discrepancy in the recommendations concerns whether to include triglycerides in an initial
screening panel. Results of recent studies are consistent with previous evidence and suggest
that, although triglyceride level is a strong univariate predictor of CHD events, its association
with such events is reduced substantially by adjustment for other risk factors. We did not
identify new evidence relevant to the appropriate interval to screen for hyperlipidemia. The use
of risk factors to select patients for treatment was not addressed in the 2001 USPSTF
recommendation. Evidence from epidemiologic studies as well as from good-quality
randomized controlled trials supports the idea that patients who have “CHD risk equivalents”
benefit from lipid-lowering therapy similar to that used in individuals who have known CHD.
New evidence demonstrates the efficacy of short-term primary prevention in high-risk
individuals older than 65 and in high-risk individuals who have lower LDL-C levels than those
enrolled in older trials. There is also strong evidence that lipid-lowering therapy is effective in
women with coronary disease or diabetes, but there is still insufficient evidence from primary
prevention trials to determine the effectiveness of lipid-lowering therapy in other low-risk and
some intermediate risk groups under-represented in older trials. New evidence about harms of
statin therapy comes from recent randomized controlled trials and FDA data analyses. The
balance of benefits and harms is clearly in favor of statin therapy among individuals enrolled in
some, but not all, randomized trials of short-term primary prevention. However, the
applicability of these findings to individuals at higher risk of adverse events is unclear, and the
long-term (>10 years) safety of statins is unknown.
10
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2.
3.
4.
U.S. Preventive Services Task Force.
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Law MR, Wald NJ, Rudnicka AR.
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Conroy RM, Pyorala K, Fitzgerald AP, et al.
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Assmann G, Schulte H, Funke H, et al. The
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Assmann G, Cullen P, Schulte H. Simple
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Wilson PW, D'Agostino RB, Levy D, et al.
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7.
Grady D, Chaput L, Kristof M. Systematic
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Ferrario M, Chiodini P, Chambless LE, et al.
Prediction of coronary events in a low
incidence population. Assessing accuracy of
the CUORE Cohort Study prediction
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Wilt T, Bloomfield H, MacDonald R, et al.
Effectiveness of statin therapy in adults with
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Shai I, Rimm EB, Hankinson SE, et al.
Multivariate assessment of lipid parameters
11
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McNeill AM, Rosamond WD, Girman CJ, et
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Heart Protection Study Collaborative Group.
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25.
Colhoun HM, Betteridge DJ, Durrington
PN, et al. Primary prevention of
cardiovascular disease with atorvastatin in
type 2 diabetes in the Collaborative
Atorvastatin Diabetes Study (CARDS):
multicentre randomised placebo-controlled
trial. Lancet. 2004;364(9435):685-696.
26.
ALLHAT Investigators. Major outcomes in
moderately hypercholesterolemic,
hypertensive patients randomized to
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Shepherd J, Blauw GJ, Murphy MB, et al.
Pravastatin in elderly individuals at risk of
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Amarenco P, Bogousslavsky J, Callahan A,
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29.
Heart Protection Study Collaborative Group.
MRC/BHF Heart Protection Study of
cholesterol-lowering with simvastatin in
5963 people with diabetes: a randomised
placebo-controlled trial. Lancet.
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30.
Sever PS, Dahlof B, Poulter NR, et al.
Anglo-Scandinavian Cardiac Outcomes
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ACAPS Group. Rationale and design for the
Asymptomatic Carotid Artery Plaque Study
(ACAPS). Control Clin Trials.
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Furberg CD, Adams HPJ, Applegate WB, et
al. Asymptomatic Carotid Artery
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Ford I, Murray H, Packard CJ, et al. Longterm follow-up of the West of Scotland
Coronary Prevention Study. N Engl J Med.
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The Lipid Research Clinics Coronary
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relationship of reduction in incidence of
coronary heart disease to cholesterol
lowering. JAMA. 1984;251(3):365-374.
Frick M, Elo O, Haapa K, et al. Helsinki
Heart Study: primary-prevention trial with
gemfibrozil in middle-aged men with
dyslipidemia. Safety of treatment, changes
in risk factors, and incidence of coronary
heart disease. N Engl J Med.
1987;317:1237-1245.
Shepherd J, Cobbe SM, Ford I, et al.
Prevention of coronary heart disease with
pravastatin in men with
hypercholesterolemia. West of Scotland
Coronary Prevention Study Group. N Engl J
Med. 1995;333(20):1301-1307.
Downs J, Clearfield M, Weis S, et al.
Primary prevention of acute coronary events
with lovastatin in men and women with
average cholesterol levels results of
AFCAPS/TexCAPS. Air Force/Texas
Coronary Atherosclerosis Prevention Study.
JAMA. 1998;279:1615-1622.
MRC/BHF Heart Protection Study of
cholesterol-lowering therapy and of
antioxidant vitamin supplementation in a
wide range of patients at increased risk of
coronary heart disease death: early safety
and efficacy experience. Eur Heart J.
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Circulation. 1994;90(4):1679-1687.
39.
Tolman K. The liver and lovastatin. Am J
Cardiol. 2002;89:1374-1380.
Clearfield M, Downs JR, Weis S, et al. Air
Force/Texas Coronary Atherosclerosis
Prevention Study (AFCAPS/TexCAPS):
efficacy and tolerability of long-term
treatment with lovastatin in women. J
Womens Health Gend Based Med.
2001;10(10):971-981.
40.
LaRosa J, Grundy S, Waters D, et al.
Intensive lipid lowering with atorvastatin in
patients with stable coronary disease. N
Engl J Med. 2005;352(14):1425-1435.
41.
Haney EM, Huffman LH, Bougatsos C, et
al. Screening for lipid disorders in children
and adolescents: systematic evidence review
for the U.S. Preventive Services Task Force.
Evidence Synthesis Number 47. Rockville,
Maryland: Agency for Healthcare Research
and Quality, July 2007. Available at:
http://www.ahrq.gov/clinic/uspstf/uspschlip.
htm. Assessed: 2008.
42.
Sever PS, Dahlof B, Poulter NR, et al.
Rationale, design, methods and baseline
demography of participants of the AngloScandinavian Cardiac Outcomes Trial.
ASCOT investigators. J Hypertens.
2001;19(6):1139-1147.
43.
Sever PS, Dahlof B, Poulter NR, et al.
Prevention of coronary and stroke events
with atorvastatin in hypertensive patients
who have average or lower-than-average
cholesterol concentrations, in the AngloScandinavian Cardiac Outcomes Trial-Lipid Lowering Arm (ASCOT-LLA): a
multicentre randomised controlled trial.
Lancet. 2003;361(9364):1149-1158.
34.
Walsh JME, Pignone M. Drug Treatment of
Hyperlipidemia in Women. JAMA
2004;291(18):2243-2252.
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Thompson PD, Clarkson P, Karas RH.
Statin-associated myopathy. JAMA.
2003;289(13):1681-1690.
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de Lemos JA, Blazing MA, Wiviott SD, et
al. Early intensive vs. a delayed conservative
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Food and Drug Administration. Steven K.
Galson, MD, MPH letter to Sidney M.
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2005.
38.
La Rosa J, He J, Vupputuri S. Effects of
statins on risk of coronary heart disease. A
meta-analysis of randomised controlled
trials. JAMA. 1999;282(24):2340-2346.
13
Table 1. Discrepancies in 2001 USPSTF and 2002/2004 ATP III Guidelines
Key Question
Target population
1) How frequent is
elevated total
cholesterol in men
younger than age 35
and women younger
than age 40, and what
proportion have an
overall 10-year risk of
cardiac events of 10%
or greater?
Initial screening panel
2) What evidence
supports the use of
triglyceride levels as part
of an initial screening
panel?
Frequency of screening
3) What are the optimal
screening intervals in
the general population
and in patients at high
risk for CHD events?
Estimating Risk
4) What risk factors
should be used to select
patients for lipid-modifying
drug therapy?
USPSTF
ATP-III
Men aged 35 and
older.
Women aged 40 and
older.
Men aged 20-34 and
women aged 20-39
who have certain risk
factors.*
Adults aged 20 and
older.
TC and HDL-C, or TC
alone if HDL-C
unavailable.
Eligible Evidence
Conclusions of Update
Observational studies (crosssectional, prospective cohort)
We did not identify new direct evidence addressing the
target population for screening. (The Task Force has
also examined a review of screening for lipid disorders
in children and adolescents up to 21 years of age,
41
It is now examining a
published in July 2007,
separate review of novel risk factors for CHD.)
TC, HDL-C, and
triglyceride level, with
calculated LDL-C.
Randomized controlled trials in
patients with elevated
triglyceride levels who would not
otherwise qualify for treatment;
Observational studies
Recent evidence is conflicting regarding the additional
contribution of a serum triglyceride level to the
identification of individuals at short-term risk for CHD
events.
Once every 5 years.
Shorter intervals for
people who have lipid
levels close to those
warranting therapy.
Longer intervals if
several previous
values have been
reassuring.
Once every 5 years if
0-1 risk factors.
Shorter intervals if
--2 or more risk
factors OR
--0 to 1 risk factors
and lipid levels close
to those warranting
therapy.
Observational studies
We did not identify new direct evidence from
observational or experimental studies regarding followup testing or the frequency of screening.
Not defined.
Four levels of risk are
defined:
CHD and CHD
equivalents.
Multiple risk factors
(2+) and 10-year risk
10-20%
Multiple risk factors
(2+) and 10-year risk
< 10%
0 to 1 risk factor and
Observational studies
Evidence from epidemiologic studies as well as from
good-quality randomized controlled trials support the
idea that patients who have “CHD risk equivalents”
benefit from lipid-lowering therapy similar to that used in
individuals who have known CHD.
For low-risk and some intermediate-risk individuals who
have elevated LDL-C or decreased HDL-C, we did not
identify new direct evidence relevant to the USPSTF
advice to treat individuals younger than age 45 or older
than age 65 if the annual incidence of coronary heart
14
Table 1. Discrepancies in 2001 USPSTF and 2002/2004 ATP III Guidelines, Continued
Key Question
USPSTF
ATP-III
Eligible Evidence
10-year risk <10%
Conclusions of Update
disease is at least 0.6% per year.
There is new direct evidence demonstrating effective
short-term primary prevention in high-risk individuals
older than 65 and in high-risk individuals who have
lower LDL-C levels than those enrolled in older trials.
There is also strong evidence that lipid-lowering therapy
is effective in women who have known coronary
disease or diabetes.
There is still insufficient direct evidence from primary
prevention trials to determine the effectiveness of lipidlowering therapy in other low-risk and some
intermediate risk groups under-represented in older
trials.
Harms of drug therapy
5) What is the current
evidence about the harms
of drug therapy for lipid
disorders?
Not addressed in
guideline. The
literature review
(through 1999)
provided a detailed
review of the adverse
effects of statins and
non-statin drug
therapy.
Randomized controlled trials and
Provides information
about side effects and long-term observational studies
refers to 2002 NHLBI
statement on safety of
statins at
www.nhlbi.nih.gov/gui
delines/cholesterol/stat
ins.htm
Statins have rare but serious harms, especially in
groups with identifiable risk factors for such events. The
balance of benefits and harms is clearly in favor of
statin therapy among individuals enrolled in some, but
not all, randomized trials of short-term primary
prevention. However, the applicability of these findings
to individuals at higher risk of adverse events is unclear.
The long-term (>10 years) safety of statins is not
known.
* Risk Factors: Diabetes; family history of cardiovascular disease before age 50 in male relatives or age 60 in female relatives; family history suggestive of familial
hyperlipidemia; or multiple coronary heart disease risk factors (e.g., tobacco use, hypertension). These are not the same risk factors as those USPSTF uses for
estimating the risk of cardiovascular events.
15
Table 2. Statin Trials that Included a Primary Prevention Group
Trial
Baseline
LDL
(mg/dL)
Study
length
(years)
% LDL
reduction
Relative risk for
coronary events
(95% CI)
5.2
25%
0.63
Drug/Dose
Risk Status
Lovastatin
20mg-40mg
Average risk, no
history of CAD
150
Pravastatin
40mg
Hypertensive
moderately high
LDL-C and at
least one
additional
CHD risk factor
145
ASCOT-LLA30,
42, 43
Fair-Good
Atorvastatin
10mg
HTN plus CHD
risk factors
133
CARDS25Good
Atorvastatin
10 mg
Type 2
diabetes, no
history of CVD
117
3.9
36%
0·63
(0·48–0·83)
HPS24
Simvastatin
40mg
History of CVD,
diabetes, or
non-coronary
vascular
disease
131
5.5
30%
0.73
(0.67–0.79)
Pravastatin
40mg
70-82 years old,
history of CHD
or risk factors
147
3.2
27%
0.85
SPARCL28
Atorvastatin
133
4.9
53%
Good
80 mg
Stroke or TIA
within 1-6
months, no
history of CHD
0.80
(0.69–0.92)
WOSCOPS21
Good
Pravastatin
40mg
High risk, no
history of CAD
192
4.9
16%
0.69
Quality
AFCAPS22
Good
ALLHAT-LLT26
Fair-Good
Good
PROSPER27
Good
(0.50–0.79)
4.8
24%
0.91
(0.79–1.04)
3.3
35%
0.71
(0.59–0.86)
(0.74–0.97)
(0.57–0.85)
16
Screening for Lipid Disorders in Adults: Selective Update of 2001 USPSTF Review
Appendix 1. Search Strategy
1 exp lovastatin/ or "lovastatin".mp.
2 simvastatin.mp.
3 Pravastatin/ or "pravastatin".mp
4 (atorvastatin or fluvastatin or rosuvastatin).mp.
5 statins.mp. or exp Hydroxymethylglutaryl-CoA Reductase Inhibitors/
6 1 or 2 or 3 or 4 or 5
7 Drug Evaluation/ or drug evaluation studies.mp.
8 comparative study/
9 7 or 8
10 6 and 9
11 limit 10 to human
12 limit 11 to english language
13 11 not 12
14 limit 13 to abstracts
15 12 or 14
16 6
17 limit 16 to (human and english language and (clinical trial or clinical trial, phase i or
clinical trial, phase ii or clinical trial, phase iii or clinical trial, phase iv or controlled clinical trial
or meta analysis or multicenter study or randomized controlled trial))
18 exp clinical trials/ or clinical trial$.tw.
19 exp cohort studies/
20 (cohort stud$ or longitudinal stud$ or prospective stud$).tw. (33965)
21 18 or 19 or 20
22 6 and 21
23 limit 22 to (human and english language)
24 17 or 23
25 15 or 24
17
Appendix 2. U.S. Preventive Services Task Force Quality Rating Criteria
Diagnostic Accuracy Studies
Criteria
•
•
•
•
•
•
•
Screening test relevant, available for primary care, adequately described
Study uses a credible reference standard, performed regardless of test results
Reference standard interpreted independently of screening test
Handles indeterminate results in a reasonable manner
Spectrum of patients included in study
Sample size
Administration of reliable screening test
Definition of ratings based on above criteria
Good:
Fair:
Poor:
Evaluates relevant available screening test; uses a credible reference standard;
interprets reference standard independently of screening test; reliability of test assessed;
has few or handles indeterminate results in a reasonable manner; includes large number
(more than 100) broad-spectrum patients with and without disease.
Evaluates relevant available screening test; uses reasonable although not best standard;
interprets reference standard independent of screening test; moderate sample size (50 to
100 subjects) and a “medium” spectrum of patients.
Has important limitation such as: uses inappropriate reference standard; screening test
improperly administered; biased ascertainment of reference standard; very small
sample size of very narrow selected spectrum of patients.
Randomized Controlled Trials (RCTs) and Cohort Studies
Criteria
•
•
•
•
•
•
•
Initial assembly of comparable groups: RCTs—adequate randomization, including
concealment and whether potential confounders were distributed equally among groups;
cohort studies—consideration of potential confounders with either restriction or
measurement for adjustment in the analysis; consideration of inception cohorts
Maintenance of comparable groups (includes attrition, cross-overs, adherence,
contamination)
Important differential loss to follow-up or overall high loss to follow-up
Measurements: equal, reliable, and valid (includes masking of outcome assessment)
Clear definition of interventions
Important outcomes considered
Analysis: adjustment for potential confounders for cohort studies, or intension-to-treat
analysis for RCTs
18
Appendix 2. U.S. Preventive Services Task Force Quality Rating Criteria, Continued
Definition of ratings based on above criteria
Good:
Fair:
Poor:
Meets all criteria: Comparable groups are assembled initially and maintained
throughout the study (follow-up at least 80 percent); reliable and valid measurement
instruments are used and applied equally to the groups; interventions are spelled out
clearly; important outcomes are considered; and appropriate attention to confounders in
analysis.
Studies will be graded “fair” if any or all of the following problems occur, without the
important limitations noted in the “poor” category below: Generally comparable groups
are assembled initially but some question remains whether some (although not major)
differences occurred in follow-up; measurement instruments are acceptable (although
not the best) and generally applied equally; some but not all important outcomes are
considered; and some but not all potential confounders are accounted for.
Studies will be graded “poor” if any of the following major limitations exists: Groups
assembled initially are not close to being comparable or maintained throughout the
study; unreliable or invalid measurement instruments are used or not applied at all
equally among groups (including not masking outcome assessment); and key
confounders are given little or no attention.
Case Control Studies
Criteria
•
•
•
•
•
•
Accurate ascertainment of cases
Nonbiased selection of cases/controls with exclusion criteria applied equally to both
Response rate
Diagnostic testing procedures applied equally to each group
Measurement of exposure accurate and applied equally to each group
Appropriate attention to potential confounding variable
Definition of ratings based on criteria above
Good:
Fair:
Poor:
Appropriate ascertainment of cases and nonbiased selection of case and control
participants; exclusion criteria applied equally to cases and controls; response rate
equal to or greater than 80 percent; diagnostic procedures and measurements accurate
and applied equally to cases and controls; and appropriate attention to confounding
variables.
Recent, relevant, without major apparent selection or diagnostic work-up bias but with
response rate less than 80 percent or attention to some but not all important
confounding variables.
Major selection or diagnostic work-up biases, response rates less than 50 percent, or
inattention to confounding variables.
19
Appendix 3. Selected Evidence from the May 2003 AHRQ Evidence Reporta on the Diagnosis and Treatment of Coronary Heart Disease in
Women, Continued
LIPIDS: CHARACTERISTICS OF CLINICAL TRIALS
Study Name, Year
N Women/
Total
(% Women)
124/717
(17)
97/497
(20)
1184/2278 (52)
Mean
Age of
Women
54
% with
CHD*
Outcomes in Women
Quality
Rating†
Clofibrate
Mean
Follow Up
(years)
6
100%
None
CHD mortality nonfatal MI
Fair
54
100%
None
Clofibrate
5
CHD mortality nonfatal MI
Fair
57
20%
TC >250 mg/dl
Colestipol
3
Fair
61
100%
TC 213-309 mg/dl
Simvastatin
5.4
441/919
(48)
61
0%
Lovastatin
2.8
22/151
(15)
NA
100%
Pravastatin
3
CARE, 199810-12
576/4159 (14)
61
100%
LDL 130-159 mg/dl
with any number of risk
factors; LDL 160-189
mg/dl with no or one
risk factor
LDL in 60-90th
percentile for age and
gender
TC <240 mg/dl and
LDL-C 115174 mg/dl
total mortality CHD
mortality
total mortality CHD
mortality nonfatal MI
revascularization
CHD events‡
total mortality
CHD mortality nonfatal MI
827/4444 (19)
ACAPS, 19947, 8
PLAC II, 19949
Pravastatin
5
LIPID, 199813-15
AFCAPS/
TEXCAPS, 199816, 17
1516/9014 (17)
997/6605 (15)
62
62
100%
0%
TC 155-271 mg/dl
TC 180-264 mg/dl LDL
130-190 mg/dl and
HDL <47 mg/dl
Pravastatin
Lovastatin
6.1
5.2
5082/20,536
(25)
5051/10,355
(49)
NA
65%
TC >135 mg/dl
Simvastatin
5
NA
14%
LDL 100-189 mg/dl
Pravastatin
4.8
Scottish Society of
Physicians, 19711
Newcastle Upon
Tyne, 19712
Colestipol Study,
19783
4S, 19944-6
HPS, 200218
ALLHAT, 200219
Lipid Entry Criterion
Key
20
Drug
total mortality
CHD mortality
nonfatal MI
total mortality
CHD mortality nonfatal MI
Revascularization
CHD events‡
CHD events‡
total mortality CHD
mortality nonfatal MI
revascularization
CHD events‡
CHD events‡
total mortality CHD
‡
events
Good
Good
Good
Good
Good
Good
Good
Fair
Appendix 3. Selected Evidence from the May 2003 AHRQ Evidence Reporta on the Diagnosis and Treatment of Coronary Heart Disease in
Women, Continued
a
Grady D, Chaput L, Kristof M. Diagnosis and Treatment of Coronary Heart Disease in Women: Systematic Reviews of Evidence on Selected Topics. Evidence Report/Technology Assessment
No. 81. (Prepared by the University of California, San Francisco-Stanford Evidence-based Practice Center under Contract No 290-97-0013.) AHRQ Publication No. 03-E037. Rockville, MD:
Agency for Healthcare Research and Quality. May 2003.
*
CHD defined as history of myocardial infarction or angina.
†
See Quality Assessment section in text.
‡
CHD events in CARE, LIPID and ALLHAT defined as CHD mortality or nonfatal MI; in 4S as CHD mortality, non fatal MI or resuscitated cardiac arrest; in AFCAPS as CHD mortality,
nonfatal MI or unstable angina or sudden cardiac death; in HPS as CHD mortality, nonfatal MI, stroke or revascularization.
Abbreviations
4S, Scandinavian Simvastatin Survival Study; ACAPS, Asymptomatic Carotid Artery Progression Study; AFCAPS/TEXCAPS, Air Force/Texas Coronary Atherosclerosis Prevention Study;
ALLHAT, Antihypertensive and Lipid-Lowering Treatment to Prevent heart Attack Trial; CARE, Cholesterol and Recurrent Events trial; CHD, coronary heart disease; CVD, cardiovascular
disease; ; HPS, Heart Protection Study; LDL, low density lipoprotein; LIPID, Long-term Intervention with Pravastatin in Ischemic Disease; mg/dl, milligrams per deciliter; MI, myocardial
infarction; N, number; NA, not available; PLAC II, Pravastatin, Lipids and Atherosclerosis in the Carotid Arteries; TC total cholesterol.
Continued-
21
Appendix 3. Selected Evidence from the May 2003 AHRQ Evidence Reporta on the Diagnosis and
Treatment of Coronary Heart Disease in Women, Continued
LIPIDS: OUTCOMES
Outcome
Secondary Prevention
Total Mortality
CHD Mortality
Nonfatal MI
CHD events*
Revascularization
Primary Prevention
Total Mortality
CHD Mortality
Nonfatal MI
CHD events*
Revascularization
Study
4S4-6
PLAC II9
Scottish Society of Physicians1
Newcastle Upon Tyne2
4S4-6
PLAC II9
CARE10-12
Scottish Society of Physicians1
Newcastle Upon Tyne2
4S4-6
PLAC II9
CARE10-12
4S4-6
CARE10-12
LIPID13-15
HPS18
4S4-6
CARE10-12
Colestipol3
ACAPS7, 8
AFCAPS/TEXCAPS16, 17
ALLHAT19
Colestipol3
ACAPS7, 8
AFCAPS/TEXCAPS16, 17
ACAPS7, 8
AFCAPS/TEXCAPS16, 17
AFCAPS/TEXCAPS16, 17
ALLHAT19
AFCAPS/TEXCAPS16, 17
RR
(95% CI)
1.11
1.18
(0.66, 1.5)
(0.03, 54.81)
0.17
0.20
0.79
1.18
0.80
(0.02, 1.34)
(0.04, 1.13)
(0.39, 1.6)
(0.03, 54.81)
(0.61, 1.05)
0.75
0.43
0.66
1.18
0.51
(0.42, 1.33)
(0.08, 2.25)
(0.48, 0.90)
(0.48, 54.81)
(0.27, 0.94)
0.68
0.60
0.87
0.81
(0.51, 0.91)
(0.37, 0.97)
(0.67, 1.13)
(0.72, 0.92)
0.52
0.82
(0.31, 0.86)
(0.64, 1.20)
0.92
0.09
1.53
0.98
(0.51, 1.69)
(0.01, 1.7)
(0.62, 3.81)
(0.83, 1.17)
1.08
0.35
2.99
(0.44, 2.63)
(0.01, 8.47)
(0.12, 73.3)
0.35
0.69
(0.04, 3.31)
(0.21, 2.28)
0.54
1.02
(0.22, 1.34)
(0.81, 1.28)
0.87
(0.33,2.31)
Key
*CHD events in CARE, LIPID and ALLHAT defined as CHD mortality or nonfatal MI; in 4S as CHD mortality, non fatal MI or
resuscitated cardiac arrest; in AFCAPS as CHD mortality, nonfatal MI, unstable angina or sudden cardiac death, and in HPS as
CHD mortality, nonfatal MI, stroke or revascularization.
Abbreviations
4S, Scandinavian Simvastatin Survival Study; ACAPS, Asymptomatic Carotid Artery Progression Study;
AFCAPS/TEXCAPS, Air Force/Texas Coronary Atherosclerosis Prevention Study; ALLHAT, Antihypertensive and
Lipid-Lowering Treatment to Prevent Heart Attack Trial; CARE, Cholesterol and Recurrent Events trial; CHD,
coronary heart disease; CI, confidence interval; HPS, Heart Protection Study; LIPID, Long-term Intervention with
Pravastatin in Ischaemic Disease; MI, myocardial infarction; NA, not available; PLAC II, Pravastatin, Lipids and
Atherosclerosis in the Carotid Arteries; RR, relative risk.
Continued-
22
Appendix 3. Selected Evidence from the May 2003 AHRQ Evidence Reporta on the Diagnosis and
Treatment of Coronary Heart Disease in Women, Continued
LIPIDS: RESULTS
Outcome
Secondary Prevention
References
RR (95% CI)
Primary Prevention
References
RR (95% CI)
Total mortality
All studies
Statin drugs
Good quality
4-6, 9
4-6, 9
4-6, 9
1.11 (0.66 1.87)
1.11 (0.66 1.87)
1.11 (0.66 1.87)
3, 7, 8, 16, 17, 19
0.74 (0.57, 0.96)
0.78 (0.60, 1.01)
0.78 (0.60, 1.01)
4-6, 9
0.64 (0.50, 0.82)
0.63 (0.48, 0.83)
0.63 (0.48, 0.83)
7, 8, 16, 17
0.79 (0.72, 0.88)
0.79 (0.72, 0.88)
0.79 (0.72, 0.88)
16, 17, 19
0.70 (0.42, 1.16)*
0.70 (0.42, 1.16)*
0.70 (0.42, 1.16)*
16, 17
7, 8, 16, 17, 19
7, 8, 16, 17
0.95 (0.62, 1.46)
0.87 (0.37, 2.00)*
0.45 (0.03, 7.00)*
CHD mortality
All studies
Statin drugs
Good quality
1, 2, 4-6, 9-12
4-6, 9-12
4-6, 9-12
4-6, 9
4-6, 9
1.07 (0.47, 2.40)
1.02 (0.11, 9.76)
1.02 (0.11, 9.76)
Nonfatal MI
All studies
Statin drugs
Good quality
1, 2, 4-6, 9-12
4-6, 9-12
4-6, 9-12
7, 8, 16, 17
7, 8, 16, 17
0.61 (0.22, 1.68)
0.61 (0.22, 1.68)
0.61 (0.22, 1.68)
CHD events†
All studies
Statin drugs
Good quality
4-6, 10-15, 18
4-6, 10-15, 18
4-6, 10-15, 18
16, 17, 19
16, 17
0.87 (0.50, 1.49)
0.87 (0.50, 1.49)
0.54 (0.22, 1.30)
Revascularization
All studies
Statin drugs
Good quality
4-6, 10-12
4-6, 10-12
4-6, 10-12
16, 17
16, 17
0.87 (0.33,2.31) ‡
0.87 (0.33,2.31) ‡
0.87 (0.33,2.31) ‡
Key
*P-value for heterogeneity <0.10
†
CHD events in CARE, LIPID and ALLHAT defined as CHD mortality or nonfatal MI; in 4S as CHD mortality, non fatal MI or
Resuscitated cardiac arrest; in AFCAPS as CHD mortality, nonfatal MI, unstable angina or sudden cardiac death, and in HPS as
CHD mortality, nonfatal MI, stroke, or revascularization. See preceding Tables for full names of studies.
‡
Only one trial provided data on this outcome
Note: Statin drugs included lovastatin, pravastatin or simvastatin
Abbreviations
CHD, coronary heart disease; CI, confidence interval; MI, myocardial infarction; RR, relative risk.
Continued-
23
Appendix 3. Selected Evidence from the May 2003 AHRQ Evidence Reporta on the Diagnosis and
Treatment of Coronary Heart Disease in Women, Continued
References for Appendix 3
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Downs JR, Clearfield M, Weis S, et al.
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24
Appendix 3. Selected Evidence from the May 2003 AHRQ Evidence Reporta on the Diagnosis and
Treatment of Coronary Heart Disease in Women, Continued
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